Thioamide substitution in the peptide backbone has several applications in studying proteolysis. Currently, we are interested in examining the ability of thioamides to inhibit aggregation in therapeutic peptide hormones, as well as investigating the positional effects these thioamide substitutions have on using thioamides as protease sensors. Thioamide substitution at positions near the scissile bond in glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), and neuropeptide Y (NPY) renders these peptides 200-1000-fold more stable toward dipeptidyl peptidase 4 (DPP-4) cleavage than the corresponding oxopeptides. In cell based assays, these thiopeptide analogs of GLP-1, GIP, and NPY are proteolytically stable and have similar potency with the parent peptide. We have also examined a thioamide GLP-1 analog in rats, where its <i>in vivo </i>potency surpasses that of native GLP-1. In order to investigate the positional effects of thioamides, we have examined several model peptides with a thioamide scanned from the P3 positon to the P3' position, and identified thioamide perturbing and non-perturbing positions.  Further mechanistic investigation showed that the primary effect of the thioamide is often to prevent binding to the protease. These studies show that thioamides can be used to improve peptide therapeutic stability against proteases, as well as be utilized as tools to study proteolysis.

Examining the effects of thioamides on proteolysis

254th National Meeting (2017)

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